The broad, long-term objectives of this research proposal is to develop new strategies and approaches for treatment of poisoning by organophosphorus insecticides. A profile of pesticide exposure reported to 56 Poison Control Centers in the United States indicated that the organophosphorus insecticides are involved in more poisonings than any other single class of pesticides. The proposal seeks to accomplish its long-term objective characterizing the inhibition, both in vivo and in vitro, of the metabolic activation of phosphorothioate insecticides (the most commonly utilized organophosphorus pesticides) by several drugs currently used to treat other disorders. It is also anticipated that this proposed research will contribute to the fundamental knowledge of those metabolic systems involved in the metabolic activation of these insecticides. The Specific Aims to be addressed are as follows: 1) To determine if certain drugs which are known to inhibit cytochrome P450- dependent metabolism of xenobiotics can inhibit bioactivation of the phosphorothioate insecticide parathion. 2) To characterize the kinetic parameters underlying the interaction between the hepatic cytochromes P450 and the drugs identified in Specific Aim 1. 3) To characterize time response and dose response relationships of inhibitors of phosphorothioate activation identified in Specific Aim 1 in order to determine if they can be effectively used as a treatment of phosphorothioate poisoning.